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Effective Enzymatic Kinetic Resolution of Alcohols using Reactive Ketene-acetal Acylating Reagents

Research Project

Project/Area Number 09557180
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Chemical pharmacy
Research InstitutionOsaka University

Principal Investigator

KITA Yasuyuki  Osaka University Graduate School of Pharmaceutical Sciences Professor, 薬学研究科, 教授 (00028862)

Co-Investigator(Kenkyū-buntansha) AKAI Shuji  Osaka University Graduate School of Pharmaceutical Sciences Research Associate, 薬学研究科, 助手 (60192457)
藤岡 弘道  大阪大学, 薬学部, 助教授 (10173410)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1998: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1997: ¥4,600,000 (Direct Cost: ¥4,600,000)
Keywordsketene acetal / acylating reagent / alcohol / lipase / kinetic resolution / asymmetrization / Diels-Alder reaction / asymmetric synthesis / 酵素的光学分割 / タンデム型反応 / フリルアルコール / 2,2-二置換プロキラルジオール / 不斉非対称化 / 不斉4級炭素
Research Abstract

In recent years, enzyme-catalyzed kinetic resolution of racemic alcohols using vinyl esters (VEs) has become one of the most commonly employed tools for asymmetric syntheses. However, in this method there remain some problems such as deactivation of enzymes by the by-product, viz., acetaldehyde and difficulties in the preparation of VEs having various acyl moieties. We have recently established a convenient method for preparation of ketene acetal acylating reagents [H2C=C(OEt)OCOR] (1) from the corresponding carboxylic acids [JCS 1, 1993]. We applied 1 to the enzymatic reactions for the first time and have disclosed an effective kinetic resolution method featuring similar to higher reactivity and selectivity than the previous methods as well as generation of a by-product, viz., ethyl acetate, which does not deactivate the enzymes [TL, 1996]. By the use of 1, this project aims at establishing practical kinetic resolution protocols and developing novel asymmetric synthetic method that co … More uld not be attained by the previous methods using VEs. The followings are summary of the results :
1. We have disclosed versatile applicability of our new method to variety of secondary
alcohols. We have also developed one-pot performing method involving in situ preparation of I followed by the kinetic resolution, which enabled us to use 1 having labile acyl moiety that was difficult to isolate.
2. Lipase-catalyzed asymmetrization of prochiral 2, 2-disubstituted 1, 3-propanediols was developed using the benzoate (1 ; R = Ph), giving high chemical and optical yields of the products bearing quaternary carbon centers. This protocol enabled us to accomplish an asymmetric synthesis of the quaternary carbon center of antitumor antibiotic, fredericamycin A, and thereby, great progress was made in our another project towards the asymmetric total synthesis of this natural product.
3. A novel lipase-catalyzed tandem asymmetric synthesis has been developed, which involves in situ preparation of 1-ethoxyvinyl methyl fumarate (1 ; R=CH=CHCO_2Me), lipase-catalyzed kinetic resolution of (2-furyl) carbinols, and intramolecular Diels-Alder reaction of thus introduced acyl moiety, providing the tricyclic adducts with up to 99% ee. We also have discovered for the first time that this lipase can affect the Diels-Alder reaction to improve enantio-and diastereo-selectivities. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Akai,Shuji: "Enzyme-catalyzed Asymmetrizatio of 2,2-Disubstituted 1,3-Propanediols Using 1-Ethoxyvinyl Esters" Tetrahedron Lett.38. 4243-4246 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kita,Yasuyuki: "Asymmetric Diels-Alder Reaction via Enzymatic Kinetic Resolution using Ethoxyvinyl Methyl Fumarate" Chem.Commun.1183-1184 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 北 泰行: "光学活性スピロ化合物の新構築 : 抗腫瘍活性天然物の全合成" ファルマシア. 34. 969-971 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kita,Yasuyuki: "Studies of Asymmetric Total Synthesis of Antitumor Antibiotic,Fredericamycin A(Review)" 有機合成化学協会誌. 56. 963-974 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akai,Shuji: "Recent Progress in the Synthesis of p-Quinones and p-Dihydroquinones through Oxidation of Phenol Derivatives. A Review" Org.Prep.Proced.Int.30. 603-629 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akai.Shuji: "Enzyme-catalyzed Asymmetrization of 2,2-Disubstituted 1,3-Propanediols Using 1-Ethoxyvinyl Esters" Tetrahedron Lett.38. 4243-4246 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kita, Yasuyuki: "Asymmetric Diels-Alder Reaction Via Enzymatic Kinetic Resolution using Ethoxyvinyl Methyl Fumarate" Chem.Commun.1183-1184 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kita, Yasuyuki: "Novel Synthesis of Optically Active Spiro Compounds : Total Synthesis of Antitumor Natural Products" Pharmacia. 34. 969-971 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kita, Yasuyuki: "Studies on Asymmetric Total Synthesis of Antitumor Antibiotic, Fredericamycin A (Review)" J.Synth.Org.Chem.Jpn.56. 963-974 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akai, Shuji: "Recent progress in the Synthesis of p-Quinones and p-Dihydroquinones through Oxidation of Phenol Derivatives. A Review" Org.Prep.Proced.Int.30. 603-629 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kita,Yasuyuki: "Asymmetric Diels-Alder reaction viaenzymatic kinetic resolution using ethoxyvinyl methyl fumarate" Chem.Commun.1183-1184 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Akai,shuji: "Enzyme-Catalyzed Asymmetrization of 2,2-Disubstituted 1,3-Propanediols Using 1-Ethoxyvinyl Esters" Tetrahedron Letters. 38. 4243-4246 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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